Intraorally Rapidly Disintergrating Tablets and Their Production

ABSTRACT

The object of the present invention is to provide, as a solid preparation for making it easy to take, thus improving patient&#39;s compliance etc., an intraorally rapidly disintegrating tablet which can be produced easily without any particular problem by a usual method of producing tablets with a usual tabletting machine, has practically unproblematic hardness, and disintegrate rapidly in the oral cavity. This tablet is produced by tabletting cores coated with a pharmaceutical disintegrating agent, wherein the core is a granule containing a water-soluble medicament or containing a medicament and a sugar.

TECHNICAL FIELD

The present invention relates to an intraorally rapidly disintegratingtablets having practically unproblematic hardness and being rapidlydisintegrating in the oral cavity. The phrase “practically unproblematichardness” refers usually to a hardness of 35 N or more. The phrase“rapidly disintegrating” refers usually to disintegration within 1minute.

BACKGROUND ART

In recent years, intra orally rapidly disintegrating tablets haveattracted attention as the form of a preparation for improving theability of a chemical to be administered, thus improving patient'scompliance etc., and various tablets have been invented.

In consideration of excellent solubility in the mouth, many ofconventional intraorally rapidly disintegrating tablets comprise sugaralcohols such as mannitol and xylitol as excipients. However, sugaralcohols easily cause obstacles such as sticking (adhesion to a punch)and binding (adhesion to a die) at the time of tabletting, and hardnessis hardly secured. Accordingly, when intraorally rapidly disintegratingtablets are produced by using sugar alcohol as an excipient, a specialprocess and a special apparatus have been employed wherein, for example,a mixture containing sugar alcohol is first moistened suitably withwater, then compression-molded under low pressure, dried and thustabletted.

On the one hand, production of intraorally rapidly disintegratingtablets, which is as close as possible to a usual method of producingtablets by tabletting dry powder or granules, is also devised. Forexample, a method of producing intraorally rapidly disintegratingtablets which comprises compression-molding a mixture containing amedicament and a disintegrating agent with fine sugar alcohol or sugarhaving an average particle diameter of 30 μm or less as a majoringredient (see WO 97/47287) and a method of producing intraorallyrapidly disintegrating tablets which comprises compression-molding amajor ingredient sugar alcohol or sugar not particularly fine, to whicha disintegrating agent and cellulose were added (see JP-A 2001-58944),have been anticipated.

However, the techniques described above are common in that dry sugaralcohol is used as a major ingredient, and thus there is necessity foran increase in the content of a highly water-repellent lubricant and forlimitation of compression pressure, in order to prevent sticking andbinding, and there is a limit to disintegrating properties and hardness.

DISCLOSURE OF INVENTION

The object of the present invention is to provide intraorally rapidlydisintegrating tablets which can be produced easily without anyparticular problem by a usual method of producing tablets with a usualtabletting machine, have practically unproblematic hardness, anddisintegrate rapidly in the oral cavity.

They found that cores coated with a pharmaceutical disintegrating agent,wherein the core is a granule containing a medicament, can be tablettedto give an intraorally rapidly disintegrating tablet meeting the objectdescribed above, and they completed the present invention.

The present invention includes, specifically, an intraorally rapidlydisintegrating tablet characterized by being produced by tablettingcores coated with a pharmaceutical disintegrating agent, wherein thecore is a granule containing a water-soluble medicament or containing amedicament and a sugar (hereinafter, the intraorally rapidlydisintegrating tablet is referred to as “the tablet of the presentinvention”).

The “sugar” which can be used in the present invention is notparticularly limited insofar as it is a pharmaceutically acceptablesugar. The examples of the sugar include sugar alcohols such asmannitol, xylitol, sorbitol, erythritol, maltitol and maltose, lactose,sucrose, glucose, and oligosaccharide. These can be used singly or as amixture of two or more thereof. Particularly, mannitol and lactose arepreferable, and combined use of mannitol and lactose is also preferable.

It can be said that the “pharmaceutical disintegrating agent” which canbe used in the present invention is a pharmaceutically acceptableadditive capable of promoting disintegration or dispersion of tabletinto secondary particles or individual particles with saliva. Thedisintegrating agent is not particularly limited insofar as it is adisintegrating agent used in pharmaceutical preparations. The examplesof the agent include crystalline cellulose, low-substitutedhydroxypropyl cellulose, carboxymethyl cellulose (carmellose), calciumcarboxymethyl cellulose (carmellose calcium), crospovidone, and starchrepresented by potato starch, wheat starch, corn starch, rice starch,hydroxypropyl starch (HPS), sodium carboxymethyl starch, andpartial-pregelatinized starch (PCS). These can be used alone or as amixture of two or more thereof. Particularly, corn starch is preferable.

The average particle diameter of the coated granules according to thepresent invention are not particularly limited, but when awater-sparingly-soluble or water-insoluble medicament is used, theaverage particle diameter is suitably 20 to 1000 μm, preferably in therange of 30 to 500 μm, more preferably in the range of 50 to 200 μm. Theparticle diameter is preferably smaller.

The medicament is not particularly limited. The examples of themedicament include the following medicaments. As used herein, the“water-soluble medicament” refers to a medicament which can be dissolvedin an amount of not less than 0.5 mg/mL, preferably not less than 1mg/mL, in water at 20° C.

1. Antipyretic, Analgesic and Antiinflammatory Agents

Indometacin, aspirin, diclofenac sodium, ketoprofen, ibuprofen,mefenamic acid, dexamethasone, sodium dexamethasone sulfate,hydrocortisone, prednisolone, azulene, phenacetin, isopropyl antipyrine,acetaminophen, benzydamine hydrochloride, phenylbutazone, flufenamicacid, sodium salicylate, choline salicylate, sasapirin, clofezone,etodolac, and ferbinac.

2. Antiulcer Agents

Sulpiride, cetraxate hydrochloride, gefarnate, irsogladine maleate,cimetidine, ranitidine hydrochloride, famotidine, nizatidine, roxatidineacetate hydrochloride, and sodium azulene sulfonate.

3. Coronary Vasodilators

Nifedipine, isosorbide dinitrate, diltiazem hydrochloride, trapidil,dipyridamole, dilazep hydrochloride,methyl-yl)-1,4-dihydropyridine-3-carboxylate, verapamil, nicardipine,nicardipine hydrochloride, and verapamil hydrochloride.

4. Peripheral Vasodilators

Ifenprodil tartrate, cinepazide maleate, cyclandelate, cinnarizine, andpentoxifylline.

5. Antibiotics

Ampicillin, amoxiline, cephalexin, erythromycmethylsuccinate,bacampicillin hydrochloride, minocycline hydrochloride, chloramphenicol,tetracycline, erythromycin, griseofulvin, cefditoren pivoxil,azithromycin, and clarithromycin.

6. Synthetic Antibacterial Agents

Nalidixic acid, piromidic acid, pipemidic acid trihydrate, enoxacin,cinoxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride,sulfamethoxazole trimethoprim,6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl]-4-oxo-4H[1,3]thiazeto[3,2-a]quinoline-3-carboxylicacid, and itraconazole.

7. Antispasmodic Agents

Propantheline bromide, atropine sulfate, oxapium bromide, timepidiumbromide, butylscopolamine bromide, trospium chloride, butropium bromide,N-methylscopolamine methyl sulfate, and methyloctatropine bromide.

8. Antitussive and Antiasthmatic Agents

Theophylline, aminophylline, methyl ephedrine hydrochloride, procaterolhydrochloride, trimetoquinol hydrochloride, codeine phosphate, sodiumcromoglycate, tranilast, dextromethorphan hydrobromide, dimemorfanphosphate, clobutinol hydrochloride, fominoben hydrochloride,benproperine phosphate, tipepidine hibenzate, eprazinone hydrochloride,clofedanol hydrochloride, ephedrine hydrochloride, noscapine,carbetapentane citrate, oxeladin tannate, isoaminil citrate, pranlukast,and fluticasone propionate.

9. Bronchodilators

Diprophylin, salbutamolsulfate, chlorprenaline hydrochloride, formoterolfumarate, orciprenaline sulfate, pirbuterol hydrochloride, hexoprenalinesulfate, bitolterol mesilate, clenbuterol hydrochloride, terbutalinesulfate, mabuterol hydrochloride, fenoterol hydrobromide, andmethoxyphenamine hydrochloride.

10. Diuretics

Furosemide, acetazolamide, trichlormethiazide, methylclothiazide,hydrochlorothiazide, hydroflumethiazide, ethiazide, cyclopentazide,spironolactone, triamterene, fluothiazide, piretanide, mefruside,etacrynic acid, azosemide, and clofenamide.

11. Muscle Relaxants

Chlorphenesin carbamate, tolperisone hydrochloride, eperisonehydrochloride, tizanidine hydrochloride, mephenesin, chlorzoxazone,phenprobamate, methocarbamol, chlormezanone, pridinol mesilate,afloqualone, baclofen, and dantrolene sodium.

12. Cerebral Metabolism Improving Agent

Mechlophenoxate hydrochloride.

13. Minor Tranquilizers

Oxazolam, diazepam, clotiazepam, medazepam, temazepam, fludiazepam,meprobamate, nitrazepam, chlordiazepoxide, and quazepam.

14. Major Tranquilizers

Sulpiride, clocapramine hydrochloride, zotepine, chlorpromadinone,haloperidol, and risperidone.

15. β-Blockers

Pindolol, propranolol hydrochloride, carteolol hydrochloride, metoprololtartrate, labetalol hydrochloride, celiprolol hydrochloride, acebutololhydrochloride, bufetolol hydrochloride, alprenolol hydrochloride,arotinolol hydrochloride, oxprenolol hydrochloride, nadolol, bucumololhydrochloride, indenolol hydrochloride, thimolol maleate, befunololhydrochloride, bupranolol hydrochloride, and carbedilol.

16. Antiarrhythmic Agents

Procainamidehydrochloride, disopyramide, ajimaline, quinidine sulfate,aprindine hydrochloride, propafenone hydrochloride, and mexiletinehydrochloride.

17. Antigout Agents

Allopurinol, probenecid, colchicine, sulfinpyrazone, benzbromarone, andbucolome.

18. Anticoagulants

Ticlopidine hydrochloride, dicumarol, and warfarin potassium.

19. Antiepileptics

Phenyloin, sodium valproate, metharbital, and carbamazepine.

20. Antihistaminics

Chlorphenylamine maleate, clemastine fumarate, mequitazine, alimemazinetartrate, and cycloheptadine hydrochloride.

21. Antiemetics

Difenidol hydrochloride, metoclopramide, domperidone, betahistinemesilate, and trimebutine maleate.

22. Antihypertensive Agents

Dimethylaminoethyl Reserpic acid hydrochloride, rescinamine, methyldopa,prazosin hydrochloride, bunazosin hydrochloride, clonidinehydrochloride, budralazine, and urapidil.

23. Sympathomimetic Agents

Dihydroergotamine mesilate, isoproterenol hydrochloride, and etilefrinehydrochloride.

24. Expectorants

Bromhexine hydrochloride, carbocysteine, ethylcysteine hydrochloride,and methylcysteine hydrochloride.

25. Oral Antidiabetic Agents

Glybenglamide, tolbutamide, glymidine sodium, troglitazone,rosiglitazone, pioglitazone hydrochloride, and epalrestat.

26. Cardiovascular System Drugs

Ubidecarenone and ATP-2Na.

27. Iron Preparations

Ferrous sulfate and dry iron sulfate.

28. Vitamins

Vitamin B₁, vitamin B₂, vitamin B₆, vitamin B₁₂, vitamin C, and folicacid.

29. Therapeutic Agents for Pollakiuria and Urinary Incontinence

Flavoxate hydrochloride, oxybutynin hydrochloride, terodilinehydrochloride, 4-diethylamino-1,1-dimethyl-2-butynyl(±)-α-cyclohexyl-α-phenylglycolate hydrochloride monohydrate.

30. Angiotensin Converting Enzyme Inhibitors

Enalapril maleate, aracepril, delapril hydrochloride, and candesartancilexetil.

31. Agent for Treating Nephritis

(3β,4α)-3,23-Dihydroxy-N-(2-methoxethyl)-18β-olean-12-en-2 8-amide(hereinafter referred to as Compound A).

32. Immune Suppressor

Tacrolimus.

33. Antimalignant Tumor Agents

Paclitaxel, docetaxel, and bicalutamide.

In the “core being a granule containing a medicament and a sugar”, thecompounding ratio of the medicament to the sugar is determined suitablysuch that the amount of the sugar is 0.3 to 1000 parts by weight,preferably 0.6 to 500 parts, based on 1 part of the medicament.

The amount of the pharmaceutical disintegrating agent blended variesdepending on the particle size of the core, and is not particularlylimited insofar as the core is coated therewith, but when the amount istoo large, the moldability and the ability of the tablet of the presentinvention to be administered are affected, and thus the pharmaceuticaldisintegrating agent is applied preferably in a form as thin as possibleonto the whole of the core. The phrase “the core is coated with thepharmaceutical disintegrating agent” refers to a state in which almostall the surface of the core is sealed with the pharmaceuticaldisintegrating agent.

The amount of the medicament incorporated into the tablet of the presentinvention can be suitably determined depending on the application methodand dose of the medicament to be applied.

In the tablet of the present invention, a third additive can be suitablyblended in such a range that the disintegrating property is maintained.The additive includes, for example, a fluidizing agent, a lubricant, acoloring agent, an aromatic, an adsorbent, a stabilizer, an antioxidant,a pH adjusting agent, a surfactant, a buffering agent, a tastecorrective, a sweetener, a foaming agent, a preservative, anacidic-taste agent and a tonic, and these additives can be contained ina suitable amount depending on necessity.

The fluidizing agent includes, for example, long-chain fatty acids suchas stearic acid; monoglycerides, diglycerides and triglycerides oflong-chain (C10 to C22) fatty acids; higher fatty alcohols such ascarnauba wax, polyoxyethylene hydrogenated castor oil, stearyl alcoholetc., wax such as cetanol; and lecithins, sodium lauryl sulfate, andthese can be contained in an amount of, for example, 20 wt % or less, inthe tablet of the present invention. The lubricant includes, forexample, stearic acid, magnesium stearate, aluminum stearate, aluminummonostearate, calcium stearate, stearyl alcohol, talc, titanium oxide,light silicic anhydride, hydrous silicon dioxide, magnesium silicate,synthetic aluminum silicate, calcium hydrogen phosphate, sucrose esterof fatty acids, hydrogenated castor oil, hydrogenated rapeseed oil,carnauba wax, beeswax, corn starch, polyethylene glycol,microcrystalline wax, and sodium lauryl sulfate. The lubricant can becontained in an amount of, for example, 3 wt % or less in the tablet ofthe present invention. The coloring agent includes, for example, ironsesquioxide, yellow iron sesquioxide, titanium oxide and tar dye. Thecoloring agent can be contained in an amount of, for example, 1 wt % orless in the tablet of the present invention. The aromatic includes, forexample, fennel oil, orange oil, cinnamon oil, clove oil, turpentineoil, peppermint oil, eucalyptus oil and lemon oil, and can be containedin an amount of, for example, 3 wt % or less in the tablet of thepresent invention. The adsorbent includes, for example, light silicicanhydride, calcium silicate, anhydrous calcium phosphate andprecipitated calcium carbonate; the stabilizer includes, for example,cyclodextrin and sodium edetate; the antioxidant includes, for example,tocopherol, ascorbic acid and cysteine hydrochloride; the pH adjustingagent includes, for example, phosphate, acetate, carbonate, citrate,tartrate, fumarate and amino acid salt; the surfactant includes, forexample, sodium lauryl sulfate, polysorbate 80, polyoxyethylenehydrogenated castor oil and polyoxyethylene (160) polyoxypropylene (30)glycol; the buffering agent includes, for example, ascorbic acid, sodiumchloride, potassium chloride and sodium carbonate; the taste correctiveincludes, for example, lactose, sucrose, glucose, mannitol, fructose,sorbitol, aspartame, saccharine, sodium saccharine, glycyrrhizate,citrate, tartrate, cocoa butter and sodium glutamate; the sweetenerincludes, for example, sodium saccharine, aspartame, dipotassiumglycyrrhizate and stevia (sucrose); the foaming agent includes, forexample, sodium bicarbonate and potassium bicarbonate; the preservativeincludes, for example, benzoate, paraoxybenzoate, salicylate and sodiumedetate; the acidic-taste agent includes, for example, citrate,tartrate, malic acid and ascorbic acid; and the tonic includes, forexample, menthol, peppermint oil, cinnamon oil, fennel oil and camphor.

The form of the tablet of the present invention is not particularlylimited, and the tablet is formed in shapes such as round shapes or oddshapes such as ellipse, doughnut etc. The tablet can be also formed intoa scored tablet. The thickness of the tablet is not particularly limitedeither, but is suitably 1 to 10 mm, preferably 2 to 8 mm. Generally, thetablet is excellent in rapid disintegrating properties as the thicknessof the tablet is decreased. The size of the tablet is not particularlylimited either, but the minor axis (or the diameter when the tablet iscircular) is suitably in the range of 6 to 20 mm, preferably 8 to 12 mm.

The tablet of the present invention can be produced for example byapplying the pharmaceutical disintegrating agent in a usual manner ontothe core being a granule containing a medicament, then drying it, andtabletting the resulting coated granules in a usual manner with a fluidbed granulating machine.

The core being a granule containing a water-soluble medicament or thecore being a granule containing a medicament and a sugar can be producedfor example by granulating and drying a medicament, a sugar etc. as thestarting materials in a usual manner. The granulation dryer includes,for example, a fluidizing granulation dryer and a tumbling fluidizinggranulation dryer.

Coating with the pharmaceutical disintegrating agent can also beconducted after production of the core, but may be conducted bygranulating and drying continuously in an analogous manner while thecore is produced.

When the core is to be coated with the pharmaceutical disintegratingagent, a pharmaceutically acceptable binder can be added in a suitableamount for the purpose of facilitating the binding of the core to thepharmaceutical disintegrating agent, and addition of the binder ispreferable. The binder is not particularly limited insofar as it is usedin pharmaceutical preparations. Specific examples include liquid starchglue, methyl cellulose, hydroxypropyl cellulose (HPC-SSL, HPC-SL, HPC-Letc.), hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose(sodium carmellose), gum arabic, gelatin, agar, tragacanth, sodiumalginate, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol andpolyethylene glycol. These can be used alone or as a mixture of two ormore thereof. Particularly, hydroxypropyl cellulose is preferable.Further, sugar such as lactose can also be incorporated into the binder.The binder can be added in the state of solution or slurry.

The method of mixing the respective components is not particularlylimited, and can be carried out by using a frequently used mixer.

The method of tabletting is not particularly limited, and the method canbe conducted by employing a frequently used rotary tabletting machine,hydraulic pressing machine or single-punch tabletting machine forexample. The tabletting pressure is fundamentally not different from themolding pressure in usual tablet production, and is suitably in therange of 3 to 25 kN/cm², preferably in the range of 8 to 17 kN/cm². Thetablet of the present invention may be produced even if the tablettingpressure is lower than 3 kN/cm² or higher than 25 kN/cm², but when thetabletting pressure is too low, the desired hardness of the tablet maynot be obtained. On the other hand, when the pressure is too high,tablet hardly rapidly disintegrating in the oral cavity may be obtained.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention is described in more detail byreference to the Examples, Comparative Examples and Test Example. As amatter of course, the present invention is not limited to the followingexamples.

Example 1

6 g of irsogladine maleate, 225 g of D-mannitol (Mannit P, averageparticle diameter about 60 μm (manufactured by Towa Chemical IndustryCo., Ltd.), which is used hereinafter unless otherwise specified) and159 g of lactose (HMS, average particle diameter about 60 μm, which isused hereinafter) were fed into a fluid bed granulation dryer (MP-01model (manufactured by Powrex), which is used hereinafter) andgranulated while spraying 121.5 g of purified water (binder solution)containing 4.5 g of hydroxypropyl cellulose (HPC-SSL (manufactured byNippon Soda Co., Ltd.), which is used hereinafter) and 9 g of lactose,thus forming cores, and when the volume of the binder solution wasreduced to ⅓, 45 g of corn starch (manufactured by Nihon Shokuhin KakoCo., Ltd. and used hereinafter) was added gradually to the granulationdryer to coat the cores with the corn starch, followed by a drying step,whereby coated granules were obtained. 1.5 g of magnesium stearate(manufactured by Taihei Chemical Industrial Co., Ltd. and usedhereinafter) was added to 300 g of the coated granules to give mixedpowder which was then tabletted (Correct 12HUK, compression pressure14.98 kN/cm² (149.8 MPa) manufactured by Kikusui Seisakusho Ltd. andused hereinafter) into the tablets (300 mg/tablet) of 10 mmφ in diameteraccording to the present invention.

Example 2

6 g of irsogladine maleate, 225 g of D-mannitol and 159 g of lactosewere fed into a fluid bed granulation dryer and granulated whilespraying 121.5 g of purified water (binder solution) containing 4.5 g ofhydroxypropyl cellulose and 9 g of lactose, and when the volume of thebinder solution was reduced to ⅓, 45 g of hydroxypropyl starch (HPS101manufactured by Freund Sangyo) was added gradually to the granulationdryer, followed by a drying step, whereby coated granules were obtained.1.5 g of magnesium stearate was added to 300 g of the coated granules togive mixed powder which was then tabletted into the tablets (300mg/tablet) of 10 mmφ in diameter according to the present invention.

Example 3

6 g of irsogladine maleate, 225 g of D-mannitol and 159 g of lactosewere fed into a fluid bed granulation dryer and granulated whilespraying 121.5 g of purified water (binder solution) containing 4.5 g ofhydroxypropyl cellulose and 9 g of lactose, and when the volume of thebinder solution was reduced to ⅓, 45 g of rice starch (Micropearlmanufactured by Shimada Kagaku Co., Ltd.) was added gradually to thegranulation dryer, followed by a drying step, whereby coated granuleswere obtained. 1.5 g of magnesium stearate was added to 300 g of thecoated granules to give mixed powder which was then tabletted into thetablets (300 mg/tablet) of 10 mmφ in diameter according to the presentinvention.

Example 4

6 g of irsogladine maleate, 225 g of D-mannitol and 159 g of lactosewere fed into a fluid bed granulation dryer and granulated whilespraying 121.5 g of purified water (binder solution) containing 4.5 g ofhydroxypropyl cellulose and 9 g of lactose, and when the volume of thebinder solution was reduced to ⅓, 45 g of fine crystalline cellulose(Avicel PH-101 manufactured by Asahi Kasei Corporation) was addedgradually to the granulation dryer, followed by a drying step, wherebycoated granules were obtained. 1.5 g of magnesium stearate was added to300 g of the coated granules to give mixed powder which was thentabletted into the tablets (300 mg/tablet) of 10 mmφ in diameteraccording to the present invention.

Example 5

6 g of irsogladine maleate, 225 g of D-mannitol and 159 g of lactosewere fed into a fluid bed granulation dryer and granulated whilespraying 121.5 g of purified water (binder solution) containing 4.5 g ofhydroxypropyl cellulose and 9 g of lactose, and when the volume of thebinder solution was reduced to ⅓, 45 g of carboxymethylcellulose (NS-300manufactured by Gotoku Chemical Company Ltd.) was added gradually to thegranulation dryer, followed by a drying step, whereby coated granuleswere obtained. 1.5 g of magnesium stearate was added to 300 g of thecoated granules to give mixed powder which was then tabletted into thetablets (300 mg/tablet) of 10 mmφ in diameter according to the presentinvention.

Example 6

6 g of irsogladine maleate, 225 g of D-mannitol and 159 g of lactosewere fed into a fluid bed granulation dryer and granulated whilespraying 121.5 g of purified water (binder solution) containing 4.5 g ofhydroxypropylmethyl cellulose (TC-SE manufactured by Shin-Etsu ChemicalCo., Ltd.) and 9 g of lactose, and when the volume of the bindersolution was reduced to ⅓, 45 g of corn starch was added gradually tothe granulation dryer, followed by a drying step, whereby coatedgranules were obtained. 1.5 g of magnesium stearate was added to 300 gof the coated granules to give mixed powder which was then tablettedinto the tablets (300 mg/tablet) of 10 mmφ in diameter according to thepresent invention.

Example 7

6 g of irsogladine maleate, 225 g of D-mannitol and 159 g of lactosewere fed into a fluid bed granulation dryer and granulated whiledownwards spraying 121.5 g of purified water (binder solution)containing 4.5 g of hydroxypropyl cellulose and 9 g of lactose, and themixture was subjected to rotating granulation at a rotor revolution rateof 300 rpm. When the volume of the binder solution was reduced to ⅓, 45g of corn starch was added gradually to the granulation dryer, followedby a drying step, whereby coated granules were obtained. 1.5 g ofmagnesium stearate was added to 300 g of the coated granules to givemixed powder which was then tabletted into the tablets (300 mg/tablet)of 10 mm in diameter according to the present invention.

Example 8

22.5 g of ambroxol hydrochloride, 217.5 g of D-mannitol and 150 g oflactose were fed into a fluid bed granulation dryer and granulated whilespraying 121.5 g of purified water (binder solution) containing 4.5 g ofhydroxypropyl cellulose and 9 g of lactose, and when the volume of thebinder solution was reduced to ⅓, 45 g of corn starch was addedgradually to the granulation dryer, followed by a drying step, wherebycoated granules were obtained. 1.5 g of magnesium stearate was added to300 g of the coated granules to give mixed powder which was thentabletted into the tablets (300 mg/tablet) of 10 mm in diameteraccording to the present invention.

Example 9

390 g of D-mannitol was fed into a fluid bed granulation dryer andgranulated while spraying 121.5 g of purified water (binder solution)containing 4.5 g of hydroxypropyl cellulose and 9 g of lactose, and whenthe volume of the binder solution was reduced to ⅓, 45 g of corn starchwas added gradually to the granulation dryer, followed by a drying step,whereby coated granules were obtained. 3 g of magnesium stearate wasadded to 300 g of the coated granules to give mixed powder which wasthen tabletted into the tablets (300 mg/tablet) of 10 mmφ in diameteraccording to the present invention.

Example 10

390 g of D-mannitol (Mannitol 35, average particle diameter of about 35μm, manufactured by Roquette Co., Ltd.) was fed into a fluid bedgranulation dryer and granulated while spraying 121.5 g of purifiedwater (binder solution) containing 4.5 g of hydroxypropyl cellulose and9 g of lactose, and when the volume of the binder solution was reducedto ⅓, 45 g of cornstarch was added gradually to the granulation dryer,followed by a drying step, whereby coated granules were obtained. 3 g ofmagnesium stearate was added to 300 g of the coated granules to givemixed powder which was then tabletted into the tablets (300 mg/tablet)of 10 mmφ in diameter according to the present invention.

Example 11

225 g of acetaminophen, 60 g of D-mannitol and 105 g of lactose were fedinto a fluid bed granulation dryer and granulated while spraying 121.5 gof purified water (binder solution) containing 4.5 g of hydroxypropylcellulose and 9 g of lactose, and when the volume of the binder solutionwas reduced to ⅓, 45 g of corn starch was added gradually to thegranulation dryer, followed by a drying step, whereby coated granuleswere obtained. 3 g of magnesium stearate was added to 300 g of thecoated granules to give mixed powder which was then tabletted into thetablets (300 mg/tablet) of 10 mmφ in diameter according to the presentinvention.

Example 12

225 g of precipitated calcium carbonate, 105 g of D-mannitol and 60 g oflactose were fed into a fluid bed granulation dryer and granulated bydownwards spraying 121.5 g of purified water (binder solution)containing 2.25 g of polyvinyl alcohol (EG-05 manufactured by NipponGosei Kagaku) and 9 g of lactose, and the mixture was subjected torotating granulation at a rotor revolution rate of 300 rpm. When thevolume of the binder solution was reduced to ⅓, 30 g of corn starch and15 g of carboxymethyl cellulose (NS-300 manufactured by Gotoku ChemicalCompany Ltd.) were added gradually to the granulation dryer, followed bya drying step, whereby coated granules were obtained. 1.5 g of magnesiumstearate was added to 300 g of the coated granules to give mixed powderwhich was then tabletted into the tablets (300 mg/tablet) of 10 mmφ indiameter according to the present invention.

Comparative Example 1 Direct Tabletting Method

A mixed powder produced by mixing 6 g of irsogladine maleate, 225 g ofD-mannitol, 159 g of lactose, 45 g of corn starch and 2.2 g of magnesiumstearate was tabletted into comparative tablets (300 mg/tablet) of 10mmφ in diameter.

Comparative Example 2 Method of Internally Adding a Disintegrating Agent

6 g of irsogladine maleate, 225 g of O-mannitol, 159 g of lactose and 45g of corn starch were fed into a fluid bed granulation dryer, sprayedwith 121.5 g of purified water (binder solution) containing 4.5 g ofhydroxypropyl cellulose and 9 g of lactose, granulated and dried to givegranules. 1.5 g of magnesium stearate was added to 300 g of the granulesto give mixed powder which was then tabletted into comparative tablets(300 mg/tablet) of 10 mmφ in diameter.

Comparative Example 3 Method of Externally Adding a Disintegrating Agent

6 g of irsogladine maleate, 225 g of D-mannitol and 159 g of lactosewere fed into a fluid bed granulation dryer, sprayed with 121.5 g ofpurified water (binder solution) containing 4.5 g of hydroxypropylcellulose and 9 g of lactose, granulated and dried to give granules. 45g of corn starch and 1.5 g of magnesium stearate were added to 255 g ofthe granules to give mixed powder which was then tabletted intocomparative tablets (300 mg/tablet) of 10 mmφ in diameter.

Test Example

The hardness of the tablets obtained in the Examples and ComparativeExamples, the disintegration time and intraoral disintegration time in adisintegration test were measured. Further, the fluidity (good or not)of the tabletting granules, the binding properties thereof (present orabsent), and the adhesion thereof to the surface of a punch (present orabsent) at the time of production of tablets were observed.

(Hardness) Measured by using a Monsanto hardness meter. 10 tablets weremeasured, and the average value was indicated.(Disintegration time in the disintegration test) Purified water was usedas test fluid, and the disintegration time was confirmed according tothe item of Tablets in Disintegration test in Japanese Pharmacopoeia,Fourteenth Edition.(Intraoral disintegration time) The time in which the tablets weredisintegrated with only saliva in the oral cavity was measured by 3 maleadults (33-, 40- and 53-year-old).

The results are shown in Table 1.

TABLE 1 Tabletting Fluidity obstacles Disintegration during AdhesionHardness Disintegration Feel in time in oral tabletting Creaking topunch (N) time (min) oral cavity cavity (sec) Example 1 good absentabsent 44.1 0.6 good 40-45 Example 2 good absent absent 49.0 0.9 good45-50 Example 3 good absent absent 54.9 1.0 good 50-60 Example 4 goodabsent absent 62.7 0.6 good 55-60 Example 5 good absent absent 40.1 0.5good 30-35 Example 6 good absent absent 40.2 1.0 good 50-60 Example 7good absent absent 43.1 0.6 good 40-45 Example 8 good absent absent 46.11.0 good 35-40 Example 9 good absent absent 45.1 1.0 good 35-40Example10 good absent absent 51.0 1.0 good 35-40 Example11 good absentabsent 50.0 0.6 good 40-45 Example12 good absent absent 42.1 0.9 good40-50 Comparative bad present present 18.6 0.7 — — Example 1 Comparativegood present absent 20.6 0.8 — — Example 2 Comparative bad presentpresent 35.3 0.8 — — Example 3

As described above, the tablets of the present invention could beproduced excellently without tabletting obstacles, had hardness withoutany practical problem, and were disintegrated rapidly in the oralcavity.

1.-5. (canceled)
 6. A method of producing an intraorally rapidlydisintegrating tablet, comprising the following steps: a. producing acore containing an active ingredient and at least one sugar, orcontaining a water soluble active ingredient; b. coating the core with apharmaceutically acceptable powdered disintegrating agent to form agranule; and c. tableting the granule.
 7. The method of claim 6, whereinthe pharmaceutically acceptable disintegrating agent is a compoundselected from the grout) consisting of crystalline cellulose,low-substituted hydroxypropyl cellulose, carboxymethyl cellulose,calcium carboxymethyl cellulose, crospovidone and starch represented bypotato starch, wheat starch, corn starch, rice starch, hydroxypropylstarch, sodium carboxymethyl starch and partial-pregelantinized starch.8. The method of claim 6, wherein the sugar is selected from the groupconsisting of sugar alcohol represented by mannitol, xylitol, sorbitol,eryritol, maltitol and maltose; lactose, sucrose, glucose, andoligosaccharide.
 9. The method of claim 6, wherein the average particlediameter of the granules is in the range of 20 to 1000 μm.
 10. Themethod of claim 6, wherein the thickness of the tablet is in the rangeof 1 to 10 mm.